Discussion
Based on a systematic search, ours is the first systematic review and
meta-analysis aiming to summarize current knowledge on the role of outer
(environmental) and inner layer (human microbiota) biodiversity in the
development of asthma, wheezing, and allergic sensitization. The
systematic review and meta-analysis showed a protective trend of
exposure to high environmental biodiversity on the development of
asthma, wheezing, and allergic sensitization. Although the evidence on
the effect of inner layer biodiversity suggested that bacterial
diversity was slightly higher among individuals with asthma, there was
no clear evidence of a significant association between inner layer
biodiversity and the risk of asthma, wheezing or allergic sensitization.
Validity of results
In addition to the four databases, we also searched the reference lists
of all the relevant articles identified. Our meta-analysis included also
evidence from longitudinal studies on biodiversity and respiratory
outcomes,17, 18, 20-26 which allowed assessment of the
time-dependent effects related to outer and inner layer biodiversity on
the development of asthma, wheezing, and allergic sensitization. Both
funnel plot and Egger’s test showed an asymmetric pattern when
addressing the effect of exposure to bacterial richness (outer layer
biodiversity), but no significant publication bias was observed for the
other exposure indicators.
The small number of studies included in the meta-analysis did not allow
conduction of subgroup analyses. The different sampling methods applied
and different types of samples (including stool and airway samples) may
also complicate the comparison of different studies. We used NOS to
evaluate the risk of bias.13 Overall, the rather low
scores on the quality scale were achieved (Table S1). Study
design-related limitations were largely due to potential unadjusted
confounding, which varied from study to study, as well as due to
self-reported outcomes, which may have increased heterogeneity in the
summary estimates of the present study. In addition, heterogeneity and
validity of self-reported outcomes may lead to information bias. The
variation in the outcome assessment method may have had impact on the
ability to reach consistent summary effect estimates, which on the other
hand may have contributed to heterogeneity of the study results.
However, as there were only a limited number of studies identified, we
were not able to perform sensitivity analysis according to the outcome
definitions.
Synthesis with previous
knowledge
Although the evidence on the role of biodiversity in the development of
respiratory outcomes was inconsistent, the findings of the present
systematic search and meta-analysis suggested that the effects related
to the inner and outer layer biodiversity on asthma, wheezing, and
allergic sensitization were variable. However, caution is needed when
interpreting the summary results, because of small number of studies
included, as well as due to heterogeneity in definitions of exposure and
outcomes, and confounders that were adjusted for.
Previous studies have reported an association between early life
environmental exposures and airways inflammation.11,
27 These studies reported that those children who had contact with
animals and allergens during early life were less likely to develop
asthma.7, 28, 29 Furthermore, exposure to higher
environmental biodiversity, assessed based on land use or vegetation
types, has been associated with a lower risk of respiratory outcomes,
such as asthma and allergic sensitization.30-32Moreover, the biodiversity hypothesis proposed that contact with natural
environments including environmental microbiota enriches the human
microbiome, promotes immune balance, and protects from developing
allergies and/or inflammatory diseases 6. While
exposure to beneficial microbiota seems to play an important role, the
complexity of different routes of exposure to microbiota and their
timing, duration, intensity and frequency make studying the role of
outer and inner biodiversity on respiratory health
challenging.33 Several previous studies have
investigated the association between the composition of the immediate
living environment and health, and found that the composition and
diversity of environmental microbiota seem to differ among different
land use types.31, 34, 35 Environments, such as
traditional farms 36, 37 and green spaces32, 38 which contain enriched and specific microbial
exposures, may be protective against asthma and allergies. More recently
a systematic review and meta-analysis reported that the associations
between exposure to green spaces and asthma (current and ever) and
allergic rhinitis were inconsistent.39 The authors
suggested that their result may be explained by a variable balance
between the positive and negative effects related to biodiversity
exposure.39 According to Hanski et al.31, environmental biodiversity, human microbiota, and
the function of the immune system are dynamic and complex systems
including different components which interact with each other. Their
study hypothesised that the association between environmental
biodiversity and atopy reflects the immunologic responses that have been
developed by individuals with long-term exposure to specific
environmental microbiota and allergens.31 Ruff et al.40 have also suggested that the drastic changes in
modern environments and lifestyles may have reduced microbial
biodiversity and led to an imbalance of the evolutionarily processes,
which in turn may have led to more unstable and less resilient
microbiota. This change in the microbiota – dysbiosis – may,
consequently, alter the balance maintained in the gut, skin and airway
microbiomes, impair immune homeostasis and increase the risk of many
chronic inflammatory diseases, such as asthma and allergic diseases.
Furthermore, the diversity and composition of human microbiota is also
influenced by several environmental exposures.7-9 A
study conducted in the Russian Karelia and the Finnish Karelia showed
significant differences in the skin and nasal microbiota composition
between the countries.41 The microbial diversity was
higher in the Russian samples than in the Finnish samples. However, no
significant associations were observed between nasal and skin microbiota
diversity and asthma among the Finnish individuals.41Consistently, a study including 72 adults participants (20 with asthma
exacerbation, 31 with non-exacerbated asthma and 21 healthy individuals)
found no statistically significant difference in Faith’s phylogenetic
diversity among these three study groups.42 A recent
cohort of mother-infant pairs from USA also showed that alpha diversity
in gut microbiome was not significantly enriched in atopic compared to
non-atopic infants.43 On the other hand, Espuela-Ortiz
et al. 44 reported significant differences in both
Shannon diversity index and Pielou index between individuals with asthma
and those without asthma. These results are consistent with the studies
conducted by Huang et al. 45 and Marri et al.46 regarding alpha diversity in airway samples. Huang
et al. 45 reported a significantly higher bacterial
diversity among individuals having asthma compared with control
individuals. The authors suggested that bacterial diversity (variation
in composition and relative abundance of specific phylotypes) is
associated with the degree of bronchial hyperresponsiveness in
individuals having asthma treated with inhaled
corticosteroids.45 Consistently with our systematic
review and meta-analysis, the results of these previous studies on
microbiota diversity and respiratory outcomes are variable.
In addition to diversity, several studies have suggested that the
composition of human and environmental microbiota may contribute to the
development of asthma and allergies.11, 22, 47, 48 The
microbiota composition may be related to a decrease in diversity,
promoting less resilient microbiota. This would alter the ecosystem
provided by the microbiota and the balance of the immune system
response.49 Furthermore, most studies addressing the
role of biodiversity in development of respiratory outcomes have
analysed only single point in time in cross-sectional studies, which has
not allowed assessment of responses of the immune system to changes in
human microbiome caused by exposure to environmental and biological
factors.50 Another important limitation in the
previous studies has been that the link between biodiversity and
pathophysiological mechanisms underlying asthma may have been confounded
by the asthma subtype and the inflammatory process.50Based on this systematic review and meta-analyses, there is a need for
population-based longitudinal studies, including: (i) cohort studies,
especially in previously under-represented populations (e.g., in Asian
and African regions); (ii) studies that apply the same or similar
definition of the outcome; (iii) studies with recruitment at an early
developmental phase (e.g. from preconception) and having a longitudinal
follow-up to identify critical periods of exposure in the life course
and to better understand mechanisms linking environmental exposures and
changes in microbiome composition, diversity and/or function to
development of asthma and allergic sensitization. Furthermore, climate
change is affecting biodiversity of both outer and inner layers. Climate
change is responsible for environmental degradation and loss of
biodiversity in plants, animals, and microorganisms, thus affecting the
distribution, composition, and interactions between microorganisms.
Climate change can also disrupt the relation between environmental
microorganisms and humans, resulting in loss of inner layer
biodiversity.51, 52 Therefore, understanding how the
interactions between outer and inner layer, biodiversity, human being,
and immune system respond to climate change is also needed for assessing
the role of biodiversity in the development of asthma, wheezing, and
allergic sensitization.